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Abstract

Background Evidence of efficacy and safety of β-blockers after thrombolysis for acute myocardial infarction (AMI) is equivocal. Newer β-blockers such as carvedilol have not been tested in this setting.

Methods and Results This study investigated the effects of acute (intravenous) and long-term (6 months, oral) treatment with carvedilol versus placebo in 151 consecutive patients with AMI. Exercise ECG, ambulatory monitoring, and two-dimensional echocardiography were performed before hospital discharge and at 3 and 6 months. All patients were followed up and cardiovascular events recorded. The Cox proportional hazards model was used to compare time from randomization with the occurrence of a cardiovascular event, and Kaplan-Meier survival curves were calculated. Carvedilol was found to be safe, and it significantly reduced cardiac events compared with placebo (18 on carvedilol and 31 on placebo, P<.02). Fifty-four patients had heart failure at study entry; 34 received carvedilol. There were no adverse effects of carvedilol therapy and no excess events in this subgroup. Carvedilol produced significant reductions in heart rate (P<.0001), blood pressure (P<.005) at rest, and rate-pressure product at peak exercise (P<.003), but exercise capacity was unchanged. Left ventricular ejection fraction was not altered significantly by carvedilol, but stroke volume was higher at pre–hospital discharge examination (63 versus 53 mL; P<.01). Diastolic filling of the left ventricle (E/A ratio) was also improved (1.2 versus 0.9; P<.001). In a subgroup with left ventricular ejection fraction <45% (n=49 patients; 24 on carvedilol and 25 on placebo), carvedilol showed attenuation of remodeling.

Conclusions Carvedilol was well tolerated and safe to use in patients immediately after AMI, including those with heart failure, and significantly improved outcome.

The effect of early treatment with β-blockers in reducing mortality and ischemic events after acute myocardial infarction (AMI) is well known. Trials with intravenous β-blockers have shown reduction of early mortality by 13% when used within 24 hours of chest pain.123 Long-term treatment also has been shown to reduce both mortality and reinfarction.45 However, all these studies were conducted before the widespread use of thrombolysis and aspirin. One large-scale, randomized trial of intravenous versus oral β-blockade in patients treated with thrombolytic drugs failed to show reduction in mortality but did show a reduction in ischemic events,6 while another showed increased adverse events in the group treated with intravenous atenolol.7 Furthermore, the negative inotropic effect of β-blockers and their potential for aggravating heart failure have, in most cases, limited their use to patients who were not in heart failure at study entry.1

Carvedilol is a unique multiple-action drug, a nonselective β-blocker with additional vasodilating properties caused by α1 blockade.8 It is an effective antianginal9 and antihypertensive agent.10 Previous studies have shown that carvedilol improves both idiopathic and ischemic congestive heart failure1112 and confers beneficial effects in patients with left ventricular dysfunction.13 Furthermore, recent studies have shown a large mortality benefit (65%) after carvedilol therapy14 when added to conventional treatment for congestive heart failure. Additionally, carvedilol affects the lipid profile favorably.15 It has also been shown to be beneficial in renal dysfunction16 and significantly limit infarct size in animal models.17 Furthermore, it is a potent antioxidant and hence may reduce damage caused by free radical generation.18

Thrombolysis and antiplatelet therapy have significantly reduced mortality after AMI.1920 Reperfusion of the occluded coronary artery produces myocardial salvage; however, the “salvaged” myocardium remains at risk of future ischemic events.1921 A drug with the properties demonstrated by carvedilol and one that may be safely given intravenously to most patients, including those in moderately severe heart failure,22 may be ideally suited to reduce both acute and long-term complications after AMI.

The primary aim of the study was to compare a group of patients with proven myocardial infarction treated with carvedilol with a matched cohort on placebo with respect to the time of development of one of several cardiovascular end points. Secondary objectives included evaluation of the safety of the drug as judged by incidence and nature of side effects and hematologic, biochemical, and ECG screening as well as evaluation of efficacy as judged by exercise capacity, hemodynamics, and systolic and diastolic left ventricular function.

Methods

Patient Selection

Patients admitted to the coronary care unit with typical signs and symptoms suggestive of AMI, ie, chest pain, ECG changes, and serum concentration of creatine kinase and MB isoform consistent with the diagnosis, were recruited to the study. Patients were subsequently withdrawn if the cardiac enzymes failed to show the typical pattern of acute myocardial necrosis. All patients gave informed consent, and the study was approved by the hospital ethics committee.

Exclusion Criteria

Patients were excluded if they were already on α- or β-blockers and calcium antagonists or had contraindications to α- or β-blockers; if they were in Killip class IV heart failure or cardiogenic shock (classes I to III were not excluded); or if they had severe bradycardia (heart rate <45 bpm), hypotension (systolic blood pressure <90 mm Hg), second- to third-degree heart block, left bundle-branch block, severe valvular disease, insulin-dependent diabetes, renal failure (creatine >159 μmol/L), known malignancy, or other severe disease or pregnancy.

Study Design

The study was designed as a single-center, double-blind, randomized, parallel-group, placebo-controlled study with stratification for location of infarction (anterior or inferior) and thrombolysis or no thrombolysis.

Dosing and Concomitant Therapy

All patients were given aspirin and had subcutaneous heparin for 3 days. The decision regarding use of thrombolysis was left entirely to the judgment of the admitting physician. Subsequently, within 24 hours of chest pain, patients were injected intravenously with 2.5 mg of carvedilol or placebo over 15 minutes. This was followed by an oral dose of 6.25 mg carvedilol or matching placebo at 4 hours after injection and then 6.25 mg BID for 2 days. The dose was increased to 12.5 mg BID at day 3 and then maintained at 12.5 mg to 25 mg BID for the duration of the study (6 months) or until a cardiovascular end point had been reached when the drug was stopped (there was no down titration). Dose titration was performed at day 14, with carvedilol being increased to 25 mg BID if blood pressure was >120/95 mm Hg and heart rate >55 bpm. End points were defined as cardiac death; reinfarction; unstable angina; heart failure; emergency revascularization; ventricular arrhythmia requiring intervention; stroke; and additional cardiovascular therapy other than sublingual nitrates for angina, diuretics for hypertension, or continuation of preexisting ACE inhibitors, digitalis, or antiarrhythmics. However, initiation of therapy with these latter three drugs after recruitment to the study, for clinical reasons, was also considered an end point. ACE inhibitors were not routinely administered for asymptomatic left ventricular dysfunction.

Study Procedures

All patients were assessed clinically at study entry for presence or absence of heart failure on the basis of Killip criteria. They had 12-lead ECGs daily for 3 days, at hospital discharge, and at every visit (days 14, 42, 84, and 168). Exercise ECG, echocardiography, and 24-hour ambulatory ECG monitoring were performed at predischarge examination and then at days 84 and 168 (study completion). Cardiac enzymes were estimated daily for 3 days. Biochemistry and hematology were tested at admission and days 42 and 168.

Follow-up

All patients were followed up after discharge from the hospital at days 14, 42, 84, and 168 (study completion). Subsequently, all patients recruited were reviewed every 3 months (including those who dropped out before study completion) until the last patient had completed 6 months, and adverse cardiac events were documented.

Twenty-Four–Hour Ambulatory Monitoring

This was carried out with the use of a Marquette Electronics series 8500 recorder, utilizing leads CM5 and CC5. Analysis was performed with the use of a Marquette Electronics Series 8000 analyzer. Tapes were analyzed for cardiac arrhythmias, ventricular ectopic counts, and hourly averaged heart rate.

Exercise ECG

Treadmill exercise testing was performed on a computer-assisted ECG system (CASE 12, Marquette Electronics Inc). A 13-lead system (12 lead + CM5) and the modified Bruce protocol were used. The ECG was continuously monitored throughout exercise and for 6 minutes after exercise termination. Blood pressure was recorded manually every 3 minutes, and ST-segment change was measured at J+60 ms. Exercise tests were used to assess angina, ST-segment changes, exercise capacity, and rate-pressure product (heart rate times systolic blood pressure).

Echocardiography

Two-dimensional, M-mode, and Doppler echocardiography was performed with the use of a digitized system (Ultramark 9, Advance Technology Laboratories). Parasternal long- and short-axis and apical four- and two-chamber views were obtained. Doppler recordings of left ventricular inflow (peak early [E] and late [A]) velocities and outflow velocities were made from the apical four-chamber view. Left ventricular volumes, ejection fraction (Simpson’s technique), and E/A ratio were calculated according to methods described in detail elsewhere and validated in our laboratory.2324 Systolic wall thickening and endocardial wall motion at rest were scored as grade 0, normal; grade 1, mild hypokinesia; grade 2, severe hypokinesia; grade 3, akinesia; and grade 4, dyskinesia. This was graded using a 13-segment left ventricular model. Global wall motion score index was calculated by adding the wall motion score and then dividing it by the number of left ventricular segments (n=13). Wall motion score at the site of myocardial infarction was also calculated by summing the wall motion score at the infarct site.

Statistical Analysis

Sample size calculations for the primary outcome variable, time from randomization to development of any cardiovascular end point, were based on two-sided tests with a significance level of 5% and a power of 80%. It was calculated that 144 patients (72 in each group) would be required to demonstrate a 20% difference between the groups.

Primary analysis was performed to compare the time from randomization with development of any one of the cardiovascular end points on an intention-to-treat basis in all patients with confirmed myocardial infarction and who had been given at least one dose of trial medication. The logistic regression test was applied before survival analysis was performed to identify factors that could have been related to the occurrence of cardiovascular end points. The factors analyzed were treatment group, sex, race, age, and site of infarction; previous history of diabetes, hyperlipidemia, hypertension, and smoking; and time from onset of pain to thrombolysis and to infusion of carvedilol or placebo. This showed that only the treatment group had a value of P<.05 and hence, thereafter, primary efficacy analysis was performed in the intention-to-treat population with the use of the Cox proportional hazards model, considering treatment as the only factor. Wilcoxon and log rank tests were also performed in the same cohort. Separate Cox analyses were also performed for “hard” end points—death and reinfarction— and also after exclusion of revascularization and need for nonpermitted cardiovascular medication. Additionally, a subgroup analysis was performed for patients who had clinical evidence of heart failure at study entry to assess the safety and efficacy of carvedilol in this group. Furthermore, the effects of drug therapy in patients with poor left ventricular function (ie, ejection fraction <45%) were also assessed by ANOVA and Fisher’s exact test. Secondary variables were analyzed with descriptive statistics. Wilcoxon U tests were calculated in the case of continuous variables to detect differences between groups. A value of P<.05 was considered significant. The continuous variables are expressed as mean (standard deviations in parentheses).

Results

Demography

Duration of the study was from February 1992 to September 1994. Of the 416 patients screened, 265 were excluded. The main reasons for exclusion were preexisting therapy with either β-blockers (n=41) or calcium blockers (n=45), elevated creatinine (n=28), delays in admission over 24 hours (n=28), poor mobility or inability to perform exercise for any other reason (n=22), declined consent (n=17), chronic obstructive airway disease (n=15), Killip class IV heart failure or death before recruitment (n=18), and patient residence outside our catchment area (n=11). The remaining 40 had miscellaneous reasons such as malignancy, left bundle-branch block, insulin-dependent diabetes, and advanced heart block.

A total of 151 patients were randomized to either carvedilol (n=77) or placebo (n=74); 146 were analyzed for efficacy on an intention-to-treat basis. Four patients (2 from each group) were excluded because they were found not to have sustained a myocardial infarction on the basis of the criteria used; 1 patient was found to have renal failure and was not given study medication. Demographic data for the 146 patients are given in Table 1⇓. There were no differences between the carvedilol and placebo groups; neither were there any differences between the two groups with respect to previous drug therapy.

Concomitant Therapy

Most patients (95%) underwent thrombolysis with streptokinase; 7 patients received tissue plasminogen activator. All patients received aspirin, 97% received heparin, and 80% received either oral or intravenous nitrates. Diuretics were allowed during the acute phase but later only for the control of hypertension. There were no differences between the groups regarding concomitant medication. No patients were on calcium channel blockers, long-acting nitrates, or ACE inhibitors during the course of the study, since clinical requirement for these drugs was a designated end point. The majority (91%) of patients on carvedilol were on 12.5 mg BID during the study.

Cardiac End Points

Treatment Period

There were significantly fewer serious cardiac events in the group treated with carvedilol (n=18) compared with placebo (n=31) (P<.02; Cox proportional hazards model, Wilcoxon and log rank tests) despite the small number of patients studied (n=146). The breakdown of events is shown in Fig 1⇓. Even after excluding the soft end points of revascularization and requirement for nonpermitted cardiovascular medication, the effect of carvedilol therapy remained significant, with 24 events on placebo compared with 14 events on carvedilol (P<.03). This study was not powered to detect differences between hard events; however, there was a trend toward benefit, with 11 deaths or reinfarctions on placebo compared with 6 on carvedilol—a 45% reduction (P=.12). Of the 12 patients (n=8 on placebo and 4 on carvedilol) who had reinfarction, 11 occurred in the original infarct territory.

In the subgroup presenting with acute heart failure at study entry, 34 were on carvedilol and 20 on placebo. None of these patients had any adverse events related to intravenous infusion of the drug, and there was no excess of cardiac events with carvedilol during either the in-hospital phase (6 events on carvedilol, 4 on placebo) or during subsequent follow-up (13 events on carvedilol compared with 9 events on placebo) (P=NS for both). Requirement for intravenous nitrates or diuretics during the acute phase did not differ between the two groups. Additionally, in this subgroup with acute heart failure, patients on carvedilol had significantly greater left ventricular ejection fraction: 45% (10) versus 35% (12), P=.005; lower end-systolic volume: 62 (23) mL versus 80 (30) mL, P=.03; lower wall motion score index: 0.85 (0.47) versus 1.46 (0.62), P<.001; and lower wall motion score at infarct site: 7.7 (3.3) versus 12.2 (4.3), P<.001, compared with placebo, before discharge.

Kaplan-Meier survival curves for carvedilol and placebo groups are shown in Fig 2⇓. It is clear that separation between the two groups begins as early as the in-hospital (within day 7) phase, and the lines continue to separate throughout the treatment phase (6 months).

Kaplan-Meier curves showing the effect of treatment with carvedilol on event-free survival during the period on randomized therapy (6 months).

Follow-up Period

After withdrawal of treatment at 6 months, 10 patients who had been on carvedilol had cardiovascular events. Interestingly, the majority (8) of the events were ischemic (unstable angina or reinfarction), and 7 of the 10 patients had been started on treatment with either atenolol (n=4), diltiazem (n=2), nicardipine (n=3), long-acting nitrates (n=4), or a combination at study completion. The Kaplan-Meier survival curves for the full duration of the study are shown in Fig 3⇓; it is evident that the curves start to converge after carvedilol was withdrawn and that the difference between the groups no longer remains statistically significant (P>.05) despite the use of other standard anti-ischemic drugs.

Kaplan-Meier curves showing the effect of treatment with carvedilol and withdrawal of drug on event-free survival (31 months).

Electrocardiography

Carvedilol produced a significant reduction in 24-hour heart rate trend compared with placebo (Fig 4⇓) during all visits. Cardiac arrhythmia was not significantly reduced by carvedilol, but there was wide variability and this may account for the lack of difference. There were no differences between the groups at any visit regarding exercise time or ST-segment change (Table 2⇓). However, patients on carvedilol had a lower heart rate, blood pressure, and rate-pressure product at peak exercise and at maximal comparable workloads at all visits (Fig 5⇓).

Rate-pressure product at peak exercise is shown for carvedilol and placebo at predischarge examination, day 84, and day 168 (study end). Box represents first and third quartiles; horizontal line is the median, and dot represents the mean. Whisker plots represent extremes of the data.

Echocardiography

There were no differences in left ventricular ejection fraction (Table 2⇑) between the groups at any visit, but stroke volume values were greater in patients on carvedilol (P<.01) (Fig 6⇓). The diastolic function parameter, E/A ratio, was significantly greater on carvedilol than placebo at predischarge examination (P<.001), demonstrating improved left ventricular filling (Fig 7⇓).

Safety Data

Hematologic and biochemical evaluations were performed three times during the study, and there were no differences between the groups. There were also no differences between the groups regarding creatine kinase levels. There were no serious adverse events related to intravenous administration of carvedilol. Adverse events requiring withdrawal unrelated to cardiac end points were similar (ie, 4 on carvedilol and 3 on placebo). Dizziness was slightly more frequent on carvedilol (6.5% compared with 1.4%) but did not cause withdrawal from the study.

Discussion

In canine models, pretreatment with β-blocker has been shown to redistribute blood flow to the endocardium, which is usually more jeopardized by the process of ischemia.25 β-Blockers reduce rate-pressure product, thus reducing oxygen requirement, and may limit infarct size. The progress of infarction, from vessel occlusion to myocardial necrosis, is usually complete within a few hours of onset of symptoms26 and hence any intervention aimed at limiting infarct size and preventing events needs to be initiated early.

In the prethrombolytic era, a large number of trials of β-blockers, used early, intravenously, and over longer periods, showed benefits such as improvement in chest pain and reduction in infarction size27 as well as reduction in mortality.12345

However, there has been a quantum change in the management of myocardial infarction since the majority of these studies were performed. The widespread use of thrombolytic therapy and aspirin has greatly reduced mortality. It is not known whether the benefits obtained previously with β-blockers are still likely to be present. Indeed, in the TIMI II-B study there was no difference in 6-day mortality between the immediate intravenous metoprolol and delayed oral metroprolol groups, but a reduction in nonfatal reinfarction and chest pain was observed.6 However, results from the GUSTO study appear to indicate that in patients given atenolol intravenously there was an increased incidence of shock, congestive heart failure, myocardial ischemia, and requirement for pacing.7 These factors have clearly restricted the widespread use of the standard β-blocker therapy after AMI. In the GISSI-3 study,28 just 31% of patients were prescribed β-blockers after myocardial infarction, while in the AIRE study,29 the figure was even lower (22%). While the use of thrombolysis has greatly reduced mortality,1920 the salvaged myocardium in the infarct-related artery territory is likely to remain at higher risk of future events. An area of such viable but ischemic myocardium may be the cause of angina, myocardial infarction, arrhythmia, and sudden death.1921 Thus, in the thrombolytic era it may be more difficult to show mortality benefits, and one must investigate the incidence of serious ischemic complications in the postinfarction phase.

Carvedilol has demonstrated potent anti-ischemic,9 cardioprotective,17 and antioxidant18 properties. Its beneficial effects in left ventricular dysfunction are manifested in both idiopathic and ischemic heart failure,1213 unlike metoprolol30 and bisoprolol,31 which have shown benefits only in dilated cardiomyopathy. This may be due to the effect of carvedilol in improving regional wall motion abnormality in patients with ischemic left ventricular dysfunction.32 This is likely to result in functional improvement in patients with hibernating myocardium, which is often present in patients with ischemic cardiomyopathy33 and after myocardial infarction with thrombolysis.34 Alternatively, the “protective” action of carvedilol may actually lie in its effect of reducing neurohormonal activation.35

Carvedilol significantly reduced double product as the result of its combined α- and β-blocking activity; it also improved stroke volume and left ventricular diastolic function (A/E ratio) but not exercise duration or left ventricular ejection fraction. However, these patients had relatively good left ventricular function and exercise capacity, and at each stage there were fewer patients in the placebo group because of larger dropouts after events. Hence, patient selection, with clinically better patients continuing in the placebo group, may have caused this lack of difference.

Despite the small number of patients and a dose of carvedilol at the lower end of the therapeutic range, there was a potent effect in reducing serious cardiac events during the treatment phase (42%). The main reduction was of the ischemic events, ie, reinfarction, unstable angina, and urgent revascularization, thus demonstrating the effect of the drug on ischemic and jeopardized myocardium after infarction. In this context, it is of note that of the 12 patients with reinfarction (8 on placebo and 4 on carvedilol), 11 occurred at the site of the original infarction. The reduction of “hard events” was 45%, but in view of the small numbers, this failed to reach statistical significance (P=.12). Since introduction of softer events such as revascularization and nonpermitted cardiovascular medication may dilute the results, analysis was also performed with the exclusion of these end points. However, the study still remained statistically significant, with a 42% reduction in events (P<.03).

Patients with heart failure at study entry were unevenly distributed (34 on carvedilol, 20 on placebo), and this may have a bearing on the apparent failure of the drug to reduce the number of patients having heart failure as an end point. It is also worth noting that despite the large number of patients with heart failure at entry, intravenous carvedilol was well tolerated, with no dropouts after infusion. Furthermore, the patients on carvedilol derived benefit in terms of left ventricular ejection fraction improvement and decreased wall motion abnormality. The majority of earlier studies of β-blockers in AMI have excluded such patients.1 Treatment with intravenous carvedilol in patients with severe chronic congestive heart failure has shown that carvedilol reduces filling pressure.22 This finding is likely to be of influence in the design of future trials of carvedilol in high-risk patients with higher grades of heart failure who may be safely included, thus expanding the therapeutic window to patients who are likely to derive the greatest benefit.

Remodeling, associated with AMI, is characterized by deleterious alterations of left ventricular size, shape, and thickness involving the infarcted and noninfarcted segments of the myocardium,36 and this is affected by infarct size, infarct healing, and loading characteristics (left ventricular distending pressure, inotropic state, heart rate, and neuroendocrine activation).3738 Progressive remodeling is associated with worsening left ventricular function and poor prognosis.3639 Acute reperfusion (eg, thrombolysis) and ACE inhibitors reduce remodeling.3740 Preliminary studies have shown that carvedilol may reverse left ventricular wall motion abnormality in patients with ischemic heart disease with myocardial infarction.32 Furthermore, this drug produces significant reduction in neurohormonal activation in congestive heart failure.41 Our data in the subgroup of patients with ejection fraction <45% after AMI show that carvedilol may have an effect on attenuation of remodeling by decreasing left ventricular size and wall motion abnormality at the infarct site. These effects are associated with a 65% reduction in serious cardiac events.

After stopping carvedilol, 10 patients who had been on the drug subsequently had cardiac events, 8 of which were ischemic (unstable angina and reinfarction). None of the events occurred immediately after withdrawal; thus, a “rebound” phenomenon was absent. Furthermore, 6 patients had events despite treatment with atenolol or diltiazem. Finally, carvedilol had an excellent safety profile.

Conclusions

Carvedilol is a novel, multiple-action vasodilating β- and α1-blocker with additional properties of cardioprotection and free radical suppression. This study demonstrates that carvedilol is safe to use after AMI with or without associated heart failure. Carvedilol also has the potential to reduce ischemic events and mortality, but larger trials are required to further elucidate its beneficial effects.

Acknowledgments

The study was supported by educational grants from the NPH Cardiac Research Fund, Harrow, UK, and Boehringer Mannheim GmbH, Mannheim, Germany. We would like to acknowledge the assistance of Christopher Kinsey, Rita Hamill, Jenny Ralph, Minoo Shah, and Catherine Belling. We would like to thank Caroline Dore and the nursing staff of the coronary care unit. We also would like to acknowledge the late Dr Edward B. Raftery.